A proper immune response is paramount in controlling intracellular infections. Activation of T helper 1 lymphocyte (Th1) response is usually associated with eradication of the infectious agents during acute infection. A shift to a T helper 2 (Th2) profile is, however, associated with persistent infection, as documented in patients with lepromatous leprosy, disseminated tuberculosis, and leishmaniasis. Without improving the T cell responses, traditional antimicrobial treatments of these chronic infections, if available, are usually prolonged, if not life-long in some cases.
Matrine and oxymatrine are two of the natural compounds isolated from the root of the herb Sophora flavescens. These two compounds have shown antiviral activity in vitro and in vivo by scientists and clinicians. In vitro experiments have demonstrated growth inhibition of coxsackievirus B and echoviruses in cell cultures, although the mechanism has not been defined (See Chen S X, et al., Effect of Sophora flavescens on cultured beating myocardial cells of coxsackie B3 virus infected newborn rat, Chinese Journal of Infectious Diseases, 2000; 14(2), 137-140 and Chen Ting Ting, et al. Ku shen, Total alkaloid's protective effects on counteracting Coxsackievirus B infected HeLa cells, Chinese journal of experimental clinical immunology. 197; 9, 18-21).
Administration of oxymatrine to transgenic mice chronically infected with hepatitis B virus demonstrated a shift in T cell response, and therefore, the cytokine profile from Th2 to Th1, as compared to placebo-treated animals. Specifically, the levels of gamma interferon and interleukin-2 increased more than three-fold, whereas the levels of interleukin-4 and interleukin-10 decreased more than three-fold. No effect on the hepatitis B viremia, mRNA and protein levels was demonstrated in these experiments (See Yuhong et al., Antihepatitis B virus mechanism of oxymatrine J. Gastro. Hepatol. 2002; 17, 1299-1306).
Clinically, intravenous matrine has been used to treat viral myocarditis in countries such as China. In one placebo-controlled study, more than 90% of the patients with chronic Coxsackievirus B myocarditis had an improvement of cardiac function, increase in lymphocyte number and function, and loss of viral markers when treated with intravenous matrine, as compared to 0% in the placebo-treated group (Chen et al., Therapeutic effect of kangke injection on viral myocarditis and its anticoxsackie virus mechanism, Chinese Journal of Integrated Traditional and Western Medicine 1997; 17(4), 207-209).
Oxymatrine is an oral agent used for the treatment of chronic hepatitis B. The overall cure rate is about 40% after one year of treatment, comparable to that of interferon-α injection (Xie Ning Wu et al., Experimental studies of oxymatrine and its mechanisms of action in hepatitis B and C viral infections, Chinese Journal of Digestive Diseases 2004; 5(1), 12-16).
Chronic fatigue syndrome (CFS) remains an elusive disease even after more than two decades of research (Reeves W C et al., Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution, BMC Health Serv Res. 2003; 3, 25-29). A severe flu-like illness that occurrs in the majority of CFS cases, followed by persistent illness and fatigue, suggest an infectious etiology triggering and the possibly of perpetuating this syndrome. In small subsets of patients, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), HHV-6, Parvovirus B19, Brucella, Toxoplasma, Coxiella burnetii, Russ river virus and Chlamydia pneumoniae have been reported to cause prolonged fatigue, fevers and many other symptoms of CFS (Chia, J. K., The role of enterovirus in chronic fatigue syndrome, J. Clin. Path. 2005; 58, 1126-1132).
Currently, there are likely more than 7.5 million CFS patients in the United States alone. Initial analysis of 200 CFS patients suggests that CFS may have a number of potentially treatable infectious etiologies as previously reported, and enteroviruses accounted for more than half of the cases, as documented by elevated neutralizing antibody titers and positive enterovirus RNA in the peripheral blood leukocytes.
Since most CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, the presence of viral capsid protein 1 (VP1), enterovirus (EV) RNA and culturable virus in the stomach biopsy specimens of patients with CFS was evaluated. It was found that 82% ( 135/165) of CFS biopsies stained positive for VP1 within parietal cells, whereas 20% ( 7/34) of the controls stained positive for VP1 within parietal cells (p≦0.001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from six patients both at the onset of the CFS/abdominal symptoms and 2-8 years later showed positive staining in the paired specimens. EV RNA was detected in 37% ( 9/24) paraffin-embedded CFS biopsy samples; 4.8% ( 1/21) of controls had detectable EV RNA (p<0.01); 33% (⅓) of patients had detectable EV RNA from two samples taken four years apart; and more than ten stomach biopsy samples showed transient growth of non-cytopathic EV. These findings suggest that persistent EV infection is present in a high percentage of CFS patients and may be the etiologic agent responsible for the profound symptomatology.
Varying immunologic abnormalities have been long described in patients with CFS. A bias toward Th2 response has been demonstrated. In overnight cultures with or without prior polyclonal activation, a significantly higher percentage of CD8+T lymphocytes from CFS patients produced interleukin-4, interleukin-10 and gamma interferon, but not interleukin-2. When compared to control subjects, the difference was not accountable by other measurements of allergic response.